Pharmaceuticals or agricultural chemicals produced by using 2-amino-6-methylnicotinic acid as an intermediate have been described, for example, in International Publication No. WO2005/33079, Japanese Patent Application Publication No. 2010-083861, and International Publication No. WO2014/6945.
As a method for producing 2-amino-6-methylnicotinic acid, there are known methods such as a method including hydrolyzing 2-chloro-3-cyano-6-methylpyridine under an acidic condition or a basic condition and reacting the obtained 2-chloro-6-methylnicotinic acid with ammonia, and a method including reacting 2-chloro-3-cyano-6-methylpyridine with ammonia in an organic solvent such as alcohol to obtain 2-amino-3-cyano-6-methylpyridine, followed by hydrolyzing the 2-amino-3-cyano-6-methylpyridine under an acidic condition or a basic condition. These methods are described, for example, in Japanese Patent Application Publication No. 2010-083861, Chinese Patent Application Publication No. 101812016, International Publication No. WO2007/76034, Bioorganic and Medicinal Chemistry Letters, Vol. 18 (6), p. 2206 (2008), and Acta Poloniae Pharmaceutica, Vol. 38 (2), p. 145 (1981).

In the conventional production methods, a purification operation is inevitable for the reason that an unreacted ingredient remains or other reasons. In addition, the conventional production methods cannot control a by-product of the reaction, and therefore is a method for producing the target product at a low yield. Specifically, when 2-chloro-6-methylnicotinic acid reacts with an aqueous solution of ammonia, 2-hydroxy-6-methylnicotinic acid is produced as a by-product at about 15 to 20 %. For this reason, it is difficult to improve the yield of 2-amino-6-methylnicotinic acid. Meanwhile, the animation reaction of 2-chloro-3-cyano-6-methylpyridine using an organic solvent such as alcohol cannot be completed even by using a saturated ammonia solution, and therefore requires a removal of the solvent and purification by column chromatography or the like. Hence, any of the conventional production methods is not exactly an easy production method capable of obtaining a target product at a high yield with high purity. Therefore, there is a demand for the development of an easy industrial production method capable of obtaining a target product at a high yield with high purity.
The present inventors have earnestly studied to solve the aforementioned problem, and consequently have arrived at the present invention by finding that 2-amino-6-methylnicotinic acid with high purity can be obtained at high yield by: reacting 2-chloro-3-cyano-6-methylpyridine in an aqueous solution of ammonia to obtain 2-amino-6-methylnicotinamide; removing the ammonia from the reaction solution by pressure reduction or the like; and thereafter adding a base such as alkali metal hydroxide to the resultant solution to react the 2-amino-6-methylnicotinamide with the base.
Specifically, an embodiment of the present invention provides a method for producing 2-amino-6-methylnicotinic acid represented by the following formula [I]:
the method comprising:
(a) reacting 2-chloro-3-cyano-6-methylpyridine represented by the following formula [I]:
in an aqueous solution of ammonia to obtain a reaction solution containing 2-amino-6-methylnicotinamide represented by the following formula [III]:
and
(b) removing the ammonia from the reaction solution, subsequently reacting the 2-amino-6-methylnicotinamide represented by the formula [III] with a base to produce the 2-amino-6-methylnicotinic acid represented by the formula [I].
In the embodiment of the present invention, the 2-amino-6-methylnicotinic acid represented by the formula [I] is produced by a one-pot synthesis from the 2-chloro-3-cyano-6-methylpyridine represented by the formula [II].